The vinca alkaloids, a group of dimeric indoledihydroindoles, have achieved considerable prominence as marketed or experimental chemotherapeutic drugs for the treatment of susceptible carcinomas, sarcomas, and leukemias. These agents are used both alone and in combination with other oncolytic agents. As a class, the vinca alkaloids include compounds obtainable from the leaves of vinca rosea, derivatives produced by chemical modification thereof and more recently, dimeric alkaloids produced by coupling two "monomeric" indoles via a modified Polonovski reaction -- see Langlois and Potier, Tetrehedron Letters, 1099 (1976), Potier, et al., J.C.S. Chem. Comm., 670 (1975), Kutney et al., Heterocycles, 3, 205 (1975) and Atta-ur-Rahman, Tetrahedron Letters, 2351 (1976).
A majority of the known vinca alkaloids can be represented by the following formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vinblastine is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 and R.sup.5 are H and R.sup.4 is ethyl, deoxy VLB "A" is represented; where R.sup.1, R.sup.2 and R.sup.5 are the same as in deoxy VLB "A" (4'-deoxyvinblastine) but where R.sup.3 is ethyl and R.sup.4 is hydrogen, deoxy VLB "B" (4'-deoxyleurosidine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl and R.sup.4 and R.sup. 5 taken together form an .alpha.-epoxide ring, leurosine is represented; and where R.sup.1, R.sup.3, R.sup.4 and R.sup.5 are the same as in leurosine but R.sup.2 is formyl, leuroformine (N-formylleurosine) is represented.
The above-mentioned alkaloids are described in the following publications: leurosine (vinleurosine -- U.S. Pat. No. 3,370,057), VLB (vincaleukoblastine, vinblastine -- U.S. Pat. No. 3,097,137), leurosidine (vinrosidine) and vincristine (leurocristine or VCR) (both in U.S. Pat. No. 3,205,220), and deoxy VLB "A" and "B," Tetrahedron Letters, 783 (1958). Other alkaloids obtainable from vinca rosea include 4-desacetoxy vinblastine (U.S. Pat. No. 3,954,773); 4-desacetoxy-3'-hydroxyvinblastine (U.S. Pat. No. 3,944,554); leurocolombine (2'-hydroxy VLB -- U.S. Pat. No. 3,890,325) and vincadioline (3'-hydroxy VLB -- U.S. Pat. No. 3,887,565).
Two of the above alkaloids, VLB and vincristine, are now marketed as drugs for the treatment of malignancies, particularly the leukemias and related diseases in humans. Of these marketed compounds, vincristine is a most active and useful agent in the treatment of leukemias but is also the least abundant of the antineoplastic alkaloids of Vinca rosea. Jovanovics et al. -- U.S. Pat. No. 3,899,493 -- have developed an elegant oxidative procedure for converting the more abundant alkaloid VLB to vincristine employing chromic acid in acetone and acetic acid at about -60.degree. C. The same procedure has been used to prepare leuroformine (N-formylleurosine) from leurosine -- see Belgian Pat. No. 811,110. Leuroformine is currently undergoing a clinical trial in Europe, chiefly in treatment of the leukemias and of multiple myeloma.
Chemical modification of VLB and vincristine has centered around hydrolysis of the 4-acetoxy group to yield 4-desacetyl VLB (DAVLB) or 4-desacetylvincristine (DAVCR) followed by reesterification with other acyl and amino-acyl groups -- see U.S. Pat. Nos. 3,392,173 and 3,387,001--, or replacement of the C-3 ester function by an amide function -- see Belgian Pat. No. 837,390. One of the former 4-acyl derivatives, the 4-N,N-dimethylglycine ester underwent a brief clinical trial and one of the latter, vindesine, (4-desacetyl VLB C-3 carboxamide) is currently being tested clinically against a variety of neoplasms.
Other chemical modification of the VLB molecule such as hydrolysis and decarboxylation of the C-18' carbomethoxy group has resulted in a loss of anti-cancer activity as has the formation of N-oxides; i.e., pleurosine (leurosine N-oxide). Oxidative attack on VLB under temperatures higher than -60.degree. C. or in neutral or basic solution has resulted in the formation of a chemotherapeutically inactive compound, vinamidine, represented by the following formula: ##STR2##
Oxidation of VLB with MnO.sub.2 in acetone or CH.sub.2 Cl.sub.2 at ambient temperature has also yielded vinamidine. The same alkaloid has been encountered in alkaloidal fractions from Vinca rosea leaves -- see Tafur et al. J. Pharm. Sci., 64, 1953 (1975) -- but the structure assigned therein (II on page 1956) is now believed to be incorrect and the above structure more closely represents the NMR, IR, and mass spectral data obtained from physiochemical studies of the compound. Vinamidine may arise from oxidative attack on VLB in which a vincinal 4',5'-dihydroxy derivative is formed which glycol, upon further oxidation, splits between the hydroxyls(4',5'bond) to yield a ring-opened derivative such as II above.
4-Desacetyl VLB and other 4-desacetyl compounds; i.e., those in which R.sup.1 in Formula I is hydroxyl, are not oxidized to the corresponding 4-oxo derivative by the Jovanovics low-temperature chronic acid oxidation (see Cullinan -- Ser. No. 723,350). Theoretical considerations emphasize the difficulty of oxidizing the secondary hydroxyl at C-4 to a carbonyl. The ring containing the C-4 carbon is locked into position since four of the ring carbons are fused into other rings of the vindoline portion of the molecule. In order to undergo oxidation from a secondary hydroxyl to a carbonyl, the bond angles of the C-4 carbon would have to change from the tetrahedral angle (108.degree.) to the sp.sup.2 angle (120.degree.). Such a change in the fused ring environment in which the C-4 carbon finds itself would involve considerable ring strain.
It is an object of this invention to provide 4-oxo derivatives of selected 4-desacetyl vinca alkaloids utilizing oxidizing agents which are effective to oxidize the secondary alcohol at C-4 without also oxidizing the velbanamine portion of the molecule to yield a vinamidine type derivative.